Protein Conformation, Dynamics, and Folding by Computer Simulation

The three-dimensional structures (or conformations) of almost a hundred different protein molecules have been revealed in atomic detail thanks to the rapid advances that have been made in protein crystallography during the past two decades. In spite of this wealth of structural detail (60, 61), understanding how protein molecules change their conforma­ tions, vibrate in response to thermal perturbations, or fold has been hampered by the lack of theoretical and computational tools that can be used to extrapolate these functional properties of proteins from their atomic structures. The theoretical difficulties arise from the large size and intrinsic complexity of protein molecules, uncertainties about the nature and magnitude of the forces acting between atoms, lack of experience with computational methods that can simulate changes in conformation, and the absence of sufficiently accurate experimental data against which the calculations can be tested. Nevertheless, the past 15 years have witnessed considerable progress in the applications of conformational energy calculations to protein molecules. Protein molecules consist of between 500 and 10,000 hydrogen, oxygen, nitrogen, carbon, and sulphur atoms bonded together to form a long polypeptide chain. In the native conformational state, this chain is folded into a globular structure in which (a) nonbonded atoms close-pack; (b) bond lengths, bond angles, and torsion angles have the same standard values as in small molecule structures; (c) almost all hydrogen bond acceptors and donors pair to form hydrogen bonds. Stated more simply,